a new to study by Portland State University researchers is the first to show that eating a diet exclusively high in saturated fat can reprogram the mouse’s immune system, making it better able to fight infection but more susceptible to systemic inflammatory conditions, including sepsis. Brooke Naperassistant professor of biology at PSU, led the study, which was published in eLife.
The ketogenic or “keto” diet is a popular high-fat diet used for weight loss or to control epileptic seizures. This study shows that when mice eat a ketogenic diet that is high in saturated fat, it can have a significant impact on their immune systems.
a previous to study by Napier and colleagues found that mice fed a high-fat, high-sugar Western diet were more susceptible to sepsis and had a higher mortality rate than mice fed a standard diet. In the current study, researchers found similar effects in mice fed a high-fat ketogenic diet, suggesting that dietary fat may play a role in sepsis.
The researchers focused on a particular fat found in the blood of mice fed a ketogenic diet: palmitic acid, which is commonly found in animal fats and dairy products. Surprisingly, mice fed a normal diet injected with palmitic acid also became more susceptible to sepsis.
“It was just exposure to this saturated fat that made them more susceptible to mortality from sepsis,” says Napier. “The idea that you could have a specific fat in your diet that would cause such a drastic outcome in disease is incredible.”
Napier and his team then tested how exactly high levels of palmitic acid might initiate sepsis. Their first clue came when they noticed that mice fed the Western diet, mice fed the ketogenic diet, and mice treated with palmitic acid had high levels of inflammatory cytokines, immune hormones that can cause fever and systemic inflammation during sepsis.
The presence of inflammatory cytokines suggested that palmitic acid might be affecting the immune system by causing inflammation, but Napier soon discovered that the story was more complicated and more interesting than that.
A DOUBLE EDGE SWORD
The mammalian immune system has two main components: the more primitive and short-lived innate immune system and the longer-lived adaptive immune system.
When you get sick or get a vaccine, your adaptive immune system produces antibodies, preparing your body to fight off a future infection. This is a form of biological ‘memory’ that can last for months, years or even a lifetime.
Biologists recently discovered that the innate immune system can also retain memory, even though its cells only last a week to a month in the blood. The “memory” of the innate immune system comes from the alteration of stem cells in the bone marrow that produce future innate immune cells, a response called trained immunity.
In this study, Napier and colleagues learned that palmitic acid can trigger trained immunity. The fat acts as a “short pulse of inflammation” that alters the function of stem cells in the mouse bone marrow so that they produce more inflammatory innate immune cells in the future. This means that when the innate immune system encounters a second inflammatory stimulus later on, it responds much more strongly. Sometimes, as in the case of sepsis, this response is too strong.
“Our model is the first time anyone has shown that a dietary component can provide this first pulse of inflammation,” says Napier. “Fat is reprogramming its stem cells to produce more inflammatory innate immune cells, and those innate immune cells, when put into this disease model of sepsis, produce more cytokines, more fever, and higher mortality rates.”
But that’s not the whole story, because inflammation isn’t always a bad thing.
“If you just have an infection, more inflammation is better because you can clear the infection faster,” says Napier.
The researchers found that this was the case in mice treated with palmitic acid. They were better able to fight off a Candida yeast infection than untreated mice.
“It’s this double-edged sword where if you have exposure to high fat and then exposure to a disease where more inflammation exacerbates the disease, then that’s a bad thing,” says Napier. “But if you’re in the context where you eat a lot of fat and then you have an infection and more inflammation helps you clear the infection faster, that’s a good thing.”
NOT ALL FATS ARE THE SAME
Napier and his colleagues also found that another type of fat could counteract the harmful effects of palmitic acid. Oleic acid, a polyunsaturated fat found in many plant-based oils, including olive oil, can block the synthesis of ceramide, a fatty substance that can initiate a stress response in cells and may play a role in the hyperinflammatory response that causes sepsis.
When the researchers fed the mice a ketogenic diet for two weeks, but also gave them oleic acid for the last three days, they no longer showed increased susceptibility to sepsis.
“It was absolutely shocking,” says Napier.
While more research is needed to see how the results of this study may extend to humans, these results could suggest that the types of fats a person eats could affect the function of their immune system and their susceptibility to disease.
“If you’re following a ketogenic diet that’s substantially high in dairy and red meat, you’re going to get a very high level of palmitic acid. Without countering that with polyunsaturated fats from something like olive oil, it would seem very reasonable that you could become more susceptible to sepsis,” says Napier, noting that this study is by no means a red flag against a ketogenic diet. “In the same way, if you eat a lot of palmitic acid you could also be helping to eliminate the infection in times of a global pandemic.”
These results may also have relevance for hospitals. They could lead to changes in the diets of people fed by feeding tubes, for example, or inform the best way to administer drugs that are solubilized in fatty acids. Health care providers may one day increase or decrease the ratios of oleic acid to palmitic acid for a patient, depending on their particular risk of infection or sepsis.
“We’re definitely looking at ways to apply this new science to clinical problems,” says Napier.
The lab is also exploring the effects of palmitic acid in breast milk. “Now we’re trying to understand whether the level of fat the mother eats affects the innate immune response of the weaned child because clearly such a response to fat must be evolutionarily conserved,” she says. “Our hypothesis is that palmitic acid in breast milk protects newborns from infections during weaning.”
Reference: Seufert AL, Hickman JW, Traxler SK, et al. Fortified dietary saturated fatty acids induce trained immunity through ceramide production which improves severity of endotoxemia and clearance of infection. eLife. 2022;11:e76744. do: 10.7554/eLife.76744
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